Alcohol abuse is a chronic problem in our society. Alcohol consumption can lead to alterations of brain circuitry both in drinkers and in the unborn offspring of drinking mothers. These changes can be long lasting and severely affect brain function. In fact, 1% of children are born with fetal alcohol spectrum disorder due to prenatal alcohol exposure with debilitating neurological symptoms. While it is appreciated that synaptic dysfunction is often associated with cognitive disorders and is observed during alcohol abuse, very little is known about the dynamic progression of synaptic changes and their mechanisms in the intact brain. We hypothesize that developmental alcohol exposure leads to abnormal regulation of synaptic dynamics by microglia leading to deficits in synaptic plasticity. Using imaging techniques which allow real time visualization of cellular morphology in vivo, we can, for the first time, visualize the rewiring of cortical networks in brains upon exposure to alcohol during development at the level of a single synapse and directly examine entirely novel mechanisms of this rewiring. These powerful techniques have already provided a wealth of information on the function of synapses in vivo in our laboratory, but have not been applied to the study of alcohol's effects on the brain. In order to determine how synaptic dysfunction during alcohol treatment impacts normal plasticity, we will use the visual system as a model and our current studies on ocular dominance plasticity in the mouse as the reference point for these experiments. Using these methods, we will test the following scenario: early alcohol exposure affects microglia-synapse interactions, destabilizes synaptic structure and leads to reduced plasticity in response to visual stimuli. We will quantify key aspects of alcohol- induced structurl synaptic plasticity in a third trimester exposure mouse model of fetal alcohol syndrome (Aim 1), and assay visual plasticity in this system (Aim 2). We will use a combination of in vivo functional and structural 4D imaging with histological, molecular and genetic tools which will provide unique insights into the synaptic changes that occur following early alcohol exposure. PUBLIC HEALTH RELEVANCE: Project narrative The structure of synapses is crucial to the proper functioning of the nervous system and changes in this structure are observed during brain development, learning, and in many neurological disorders. In this study we will explore how synapse structure and microglial behavior is altered in a mouse model of fetal alcohol syndrome, a devastating disorder which is accompanied by severe mental retardation. We will also determine whether dendritic spines and microglia can be therapeutic targets in the treatment of fetal alcohol syndrome.